#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
CS
proLékaře.cz / Journals / Czecho-Slovak Pathology / 2025 - 3

Cholangiocarcinoma –⁠ Morphology, Immunohistochemistry, and Genetics

Czech version

Authors: Jan Hrudka 1;  Radoslav Matěj 1,2
Authors‘ workplace: Ústav patologie, Fakultní nemocnice Královské Vinohrady, 3. lékařská fakulta Univerzity Karlovy v Praze. 1;  Ústav patologie a molekulární medicíny, Fakultní Thomayerova nemocnice, 3. lékařská fakulta Univerzity Karlovy v Praze. 2
Published in: Čes.-slov. Patol., 61, 2025, No. 3, p. 148-158
Category: Reviews Article

Overview

Cholangiocellular carcinoma (cholangiocarcinoma, CCA) is a heterogeneous group of malignant epithelial tumors of the bile ducts, with varying classifications and molecular characteristics. CCA can arise in intrahepatic, perihilar, or extrahepatic bile ducts, with its incidence rising globally, particularly in Southeast Asia due to liver fluke infections. Other risk factors include primary sclerosing cholangitis, viral hepatitis, gallstones, congenital bile duct malformations, and cirrhosis. CCA is often diagnosed at advanced stages and has a poor prognosis.

This article summarizes the complex classification systems of CCA and biliary precancerous lesions (biliary intraepithelial neoplasia, BilIN), focusing on morphology, molecular profiles, and clinical implications. It briefly addresses the differential diagnosis between CCA and BilIN, distinguishing intrahepatic from extrahepatic CCA, as well as differentiating CCA from hepatocellular carcinoma (HCC) and metastatic adenocarcinomas. Alongside selected literature, experiences from our institution using various immunohistochemical methods (CRP, S100P, IMP3) are presented, highlighting their relevance in routine practice. The majority of the article focuses on the molecular pathology of CCA, where mutation profiles differ according to anatomical subtypes. Intrahepatic CCA more frequently harbors mutations in IDH1/2, FGFR, and BAP1, while perihilar and extrahepatic CCAs are more likely to exhibit mutations in TP53, KRAS, and ERBB2. Alterations in FGFR2 and IDH1 are associated with better prognosis, while TP53 and KRAS mutations indicate worse outcomes. The article provides an overview of genetic alterations that are targetable with current oncological therapies, including FDA-approved inhibitors for FGFR2 (pemigatinib, futibatinib) and IDH1 (ivosidenib), along with inhibitors targeting BRAF, HER2, NTRK, and immunotherapies for MSI-high and TMB-high tumors. Intrahepatic CCA presents a broader spectrum of therapeutic targets, including rare fusions (ALK, RET), compared to perihilar and extrahepatic CCA, which share a poor prognosis and limited therapeutic options with pancreatic cancer. In this regard, intrahepatic CCA may become the „non-small cell lung cancer of gastrointestinal oncology.“

Keywords:

cholangiocarcinoma – intrahepatic – extrahepatic – targeted therapy – IDH1 – FGFR2

Sources
  1. Krasinskas AM. Cholangiocarcinoma. Surg Pathol Clin 2018;11 : 403–429.
  2. Saha SK, Zhu AX, Fuchs CS, Brooks GA. Forty-year trends in cholangiocarcinoma incidence in the U.s.: Intrahepatic disease on the rise. Oncologist 2016;21 : 594–599.
  3. Dušek L, Mužík J, Krejčí D. Epidemiology of gallbladder and bile duct malignancies in the Czech Republic. Cas Lek Cesk 2019;158 : 52–56.
  4. Van Dyke AL, Shiels MS, Jones GS, Pfeiffer RM, Petrick JL, Beebe-Dimmer JL, et al. Biliary tract cancer incidence and trends in the United States by demographic group, 19992013. Cancer 2019;125 : 1489–1498.
  5. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 2001;33 : 1353–1357.
  6. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014;383 : 2168–2179.
  7. Palmer WC, Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J Hepatol 2012;57 : 69–76.
  8. Blechacz B. Cholangiocarcinoma: Current knowledge and new developments. Gut Liver 2017;11 : 13–26.
  9. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas. Gastroenterology 2009;136 : 1134–1144.
  10. Amin MB, Edge S, Greene F, Byrd DR. AJCC cancer staging manual. 2017. Available: https://scholar.google.com/citations?user=CdCSWpkAAAAJ&hl=cs&oi=sra
  11. Bridgewater J, Galle PR, Khan SA, Llovet JM, Park J-W, Patel T, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol 2014;60 : 1268–1289.
  12. Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76 : 182–188.
  13. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB, Invernizzi P, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol 2016;13 : 261–280.
  14. Guedj N, Bedossa P, Paradis V. Pathology of cholangiocarcinoma. Ann Pathol 2010;30 : 455–463.
  15. Nakanuma Y, Sato Y. Hilar cholangiocarcinoma is pathologically similar to pancreatic duct adenocarcinoma: suggestions of similar background and development. J Hepatobiliary Pancreat Sci 2014;21 : 441–447.
  16. Yamanaka N, Okamoto E, Ando T, Oriyama T, Fujimoto J, Furukawa K, et al. Clinicopathologic spectrum of resected extraductal mass-forming intrahepatic cholangiocarcinoma. Cancer 1995;76 : 2449–2456.
  17. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J Hepatobiliary Pancreat Surg 2003;10 : 288–291.
  18. Liau JY, Tsai JH, Yuan RH, Chang CN, Lee HJ, Jeng YM. Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features. Mod Pathol 2014;27 : 1163–1173.
  19. Gandou C, Harada K, Sato Y, Igarashi S, Sasaki M, Ikeda H, et al. Hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma share similar histopathologies, immunophenotypes, and development-related molecules. Hum Pathol 2013;44 : 811–821.
  20. Hrudka J, Prouzová Z, Mydlíková K, Jedličková K, Holešta M, Whitley A, et al. FOXF1 as an immunohistochemical marker of hilar cholangiocarcinoma or metastatic pancreatic ductal adenocarcinoma. Single institution experience. Pathol Oncol Res 2021;27 : 1609756.
  21. Zen Y. Intrahepatic cholangiocarcinoma: typical features, uncommon variants, and controversial related entities. Hum Pathol 2023;132 : 197–207.
  22. Yu TH, Yuan RH, Chen YL, Yang WC, Hsu HC, Jeng YM. Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression. Mod Pathol 2011;24 : 810–819.
  23. Zen Y, Quaglia A, Heaton N, Rela M, Portmann B. Two distinct pathways of carcinogenesis in primary sclerosing cholangitis. Histopathology 2011;59 : 1100–1110.
  24. Sigel CS, Drill E, Zhou Y, Basturk O, Askan G, Pak LM, et al. Intrahepatic cholangiocarcinomas have histologically and immunophenotypically distinct small and large duct patterns. Am J Surg Pathol 2018;42 : 1334 –⁠ 1345.
  25. Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC. Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol 2007;31 : 907–913.
  26. Katabi N, Albores-Saavedra J. The extrahepatic bile duct lesions in end-stage primary sclerosing cholangitis. Am J Surg Pathol 2003;27 : 349–355.
  27. Lee SE, Jang JY, Lee YJ, Choi DW, Lee WJ, Cho BH, et al. Choledochal cyst and associated malignant tumors in adults: a multicenter survey in South Korea. Arch Surg 2011;146 : 1178–1184.
  28. Zen Y, Adsay NV, Bardadin K, Colombari R, Ferrell L, Haga H, et al. Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria. Mod Pathol 2007;20 : 701–709.
  29. Roa I, de Aretxabala X, Araya JC, Roa J. Preneoplastic lesions in gallbladder cancer. J Surg Oncol 2006;93 : 615–623.
  30. Nakanishi Y, Zen Y, Kondo S, Itoh T, Itatsu K, Nakanuma Y. Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm. Hum Pathol 2008;39 : 1153–1161.
  31. Wakai T, Shirai Y, Moroda T, Yokoyama N, Hatakeyama K. Impact of ductal resection margin status on long-term survival in patients undergoing resection for extrahepatic cholangiocarcinoma. Cancer 2005;103 : 1210–1216.
  32. Nakanishi Y, Kondo S, Zen Y, Yonemori A, Kubota K, Kawakami H, et al. Impact of residual in situ carcinoma on postoperative survival in 125 patients with extrahepatic bile duct carcinoma. J Hepatobiliary Pancreat Sci 2010;17 : 166–173.
  33. Sasaki R, Takeda Y, Funato O, Nitta H, Kawamura H, Uesugi N, et al. Significance of ductal margin status in patients undergoing surgical resection for extrahepatic cholangiocarcinoma. World J Surg 2007;31 : 1788–1796.
  34. Tsukahara T, Ebata T, Shimoyama Y, Yokoyama Y, Igami T, Sugawara G, et al. Residual carcinoma in situ at the ductal stump has a negative survival effect: An analysis of early-stage cholangiocarcinomas. Ann Surg 2017;266 : 126–132.
  35. Wakai T, Sakata J, Katada T, Hirose Y, Soma D, Prasoon P, et al. Surgical management of carcinoma in situ at ductal resection margins in patients with extrahepatic cholangiocarcinoma. Ann Gastroenterol Surg 2018;2 : 359–366.
  36. Xu Z, Fan X, Zhang C, Li Y, Jiang D, Hu F, et al. Residual biliary intraepithelial neoplasia without malignant transformation at resection margin for perihilar cholangiocarcinoma does not require expanded resection: a dual center retrospective study. World J Surg Oncol 2024;22 : 161.
  37. Wistuba II, Gazdar AF, Roa I, Albores-Saavedra J. P53 protein overexpression in gallbladder carcinoma and its precursor lesions: An immunohistochemical study. Hum Pathol 1996;27 : 360–365.
  38. Sica E, Shore KT, Yang L, Phelps KC, Hammer STG, Gopal P, et al. Utility of IMP3, p53, and S100P immunohistochemical stains in distinguishing reactive atypia from dysplasia in cholecystectomy specimens. Diagn Pathol 2024;19 : 129.
  39. Levy M, Lin F, Xu H, Dhall D, Spaulding BO, Wang HL. S100P, von Hippel-Lindau gene product, and IMP3 serve as a useful immunohistochemical panel in the diagnosis of adenocarcinoma on endoscopic bile duct biopsy. Hum Pathol 2010;41 : 1210–1219.
  40. Jiang H, Hu H, Tong X, Jiang Q, Zhu H, Zhang S. Calcium-binding protein S100P and cancer: mechanisms and clinical relevance. J Cancer Res Clin Oncol 2012;138 : 1–9.
  41. Hamada S, Satoh K, Hirota M, Kanno A, Ishida K, Umino J, et al. Calcium-binding protein S100P is a novel diagnostic marker of cholangiocarcinoma. Cancer Sci 2011;102 : 150–156.
  42. Riener M-O, Vogetseder A, Pestalozzi BC, Clavien PA, Probst-Hensch N, Kristiansen G, et al. Cell adhesion molecules P-cadherin and CD24 are markers for carcinoma and dysplasia in the biliary tract. Hum Pathol 2010;41 : 1558–1565.
  43. Stroescu C, Herlea V, Dragnea A, Popescu I. The diagnostic value of cytokeratins and carcinoembryonic antigen immunostaining in differentiating hepatocellular carcinomas from intrahepatic cholangiocarcinomas. J Gastrointestin Liver Dis 2006;15 : 9–14.
  44. Chan ES, Yeh MM. The use of immunohistochemistry in liver tumors. Clin Liver Dis 2010;14 : 687–703.
  45. Takahashi Y, Dungubat E, Kusano H, Ganbat D, Tomita Y, Odgerel S, et al. Application of immunohistochemistry in the pathological diagnosis of liver tumors. Int J Mol Sci 2021;22 : 5780.
  46. Durnez A, Verslype C, Nevens F, Fevery J, Aerts R, Pirenne J, et al. The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin. Histopathology 2006;49 : 138–151.
  47. Leong AS, Sormunen RT, Tsui WM, Liew CT. Hep Par 1 and selected antibodies in the immunohistological distinction of hepatocellular carcinoma from cholangiocarcinoma, combined tumours and metastatic carcinoma. Histopathology 1998;33 : 318–324.
  48. Morrison C, Marsh W Jr, Frankel WL. A comparison of CD10 to pCEA, MOC-31, and hepatocyte for the distinction of malignant tumors in the liver. Mod Pathol 2002;15 : 1279–1287.
  49. Lau SK, Prakash S, Geller SA, Alsabeh R. Comparative immunohistochemical profile of hepatocellular carcinoma, cholangiocarcinoma, and metastatic adenocarcinoma. Hum Pathol 2002;33 : 1175–1181.
  50. Niemann TH, Hughes JH, De Young BR. MOC-31 aids in the differentiation of metastatic adenocarcinoma from hepatocellular carcinoma. Cancer 1999;87 : 295–298.
  51. Proca DM, Niemann TH, Porcell AI, DeYoung BR. MOC31 immunoreactivity in primary and metastatic carcinoma of the liver. Report of findings and review of other utilized markers. Appl Immunohistochem Mol Morphol 2000;8 : 120–125.
  52. Yeh YC, Lei HJ, Chen MH, Ho HL, Chiu LY, Li CP, et al. C-reactive protein (CRP) is a promising diagnostic immunohistochemical marker for intrahepatic cholangiocarcinoma and is associated with better prognosis. Am J Surg Pathol 2017;41 : 1630–1641.
  53. Bosch FX, Ribes J, Díaz M, Cléries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127: S5–S16.
  54. van der Geest LGM, Lam-Boer J ’t, Koopman M, Verhoef C, Elferink MAG, de Wilt JHW. Nationwide trends in incidence, treatment and survival of colorectal cancer patients with synchronous metastases. Clin Exp Metastasis 2015;32 : 457–465.
  55. Riihimäki M, Hemminki A, Sundquist J, Hemminki K. Patterns of metastasis in colon and rectal cancer. Sci Rep 2016;6 : 29765.
  56. Dennis JL, Hvidsten TR, Wit EC, Komorowski J, Bell AK, Downie I, et al. Markers of adenocarcinoma characteristic of the site of origin: development of a diagnostic algorithm. Clin Cancer Res 2005;11 : 3766–3772.
  57. Kaimaktchiev V, Terracciano L, Tornillo L, Spichtin H, Stoios D, Bundi M, et al. The homeobox intestinal differentiation factor CDX2 is selectively expressed in gastrointestinal adenocarcinomas. Mod Pathol 2004;17 : 1392–1399.
  58. Dragomir A, de Wit M, Johansson C, Uhlen M, Pontén F. The role of SATB2 as a diagnostic marker for tumors of colorectal origin: Results of a pathology-based clinical prospective study. Am J Clin Pathol 2014;141 : 630–638.
  59. Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol 2000;13 : 962–972.
  60. Hrudka J, Fišerová H, Jelínková K, Matěj R, Waldauf P. Cytokeratin 7 expression as a predictor of an unfavorable prognosis in colorectal carcinoma. Sci Rep 2021;11 : 17863.
  61. Hrudka J, Kalinová M, Fišerová H, Jelínková K, Nikov A, Waldauf P, et al. Molecular genetic analysis of colorectal carcinoma with an aggressive extraintestinal immunohistochemical phenotype. Sci Rep 2024;14 : 22241.
  62. Chung YS, Jeon Y, Yoo JE, Chung T, Ryu HJ, Kim H, et al. Albumin, filamin-A and cytokeratin 19 help distinguish intrahepatic cholangiocarcinoma from extrahepatic adenocarcinoma. Hepatol Int 2023;17 : 77–85.
  63. Avadhani V, Cohen C, Siddiqui MT, Krasinskas A. A subset of intrahepatic cholangiocarcinomas express albumin RNA as detected by in situ hybridization. Appl Immunohistochem Mol Morphol 2021;29 : 175–179.
  64. Albertini E, Chillotti S, Monti G, Malvi D, Deserti M, Degiovanni A, et al. Decreasing albumin mRNA expression in cholangiocarcinomas along the bile duct tree. Pathobiology 2024;91 : 338–344.
  65. Tsai JH, Huang WC, Kuo KT, Yuan RH, Chen YL, Jeng YM. S100P immunostaining identifies a subset of peripheral-type intrahepatic cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas. Histopathology 2012;61 : 1106–1116.
  66. Aishima S, Fujita N, Mano Y, Kubo Y, Tanaka Y, Taketomi A, et al. Different roles of S100P overexpression in intrahepatic cholangiocarcinoma: carcinogenesis of perihilar type and aggressive behavior of peripheral type. Am J Surg Pathol 2011;35 : 590–598.
  67. Zou S, Li J, Zhou H, Frech C, Jiang X, Chu JSC, et al. Mutational landscape of intrahepatic cholangiocarcinoma. Nat Commun 2014;5 : 5696.
  68. Liu ZH, Lian BF, Dong QZ, Sun H, Wei JW, Sheng YY, et al. Whole-exome mutational and transcriptional landscapes of combined hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma reveal molecular diversity. Biochim Biophys Acta Mol Basis Dis 2018;1864 : 2360–2368.
  69. Churi CR, Shroff R, Wang Y, Rashid A, Kang HC, Weatherly J, et al. Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications. PLoS One 2014;9: e115383.
  70. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47 : 1003–1010.
  71. Lowery MA, Ptashkin R, Jordan E, Berger MF, Zehir A, Capanu M, et al. Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: Potential targets for intervention. Clin Cancer Res 2018;24 : 4154–4161.
  72. Ma B, Meng H, Tian Y, Wang Y, Song T, Zhang T, et al. Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma. BMC Cancer 2020;20 : 318.
  73. Javle M, Bekaii-Saab T, Jain A, Wang Y, Kelley RK, Wang K, et al. Biliary cancer: Utility of next-generation sequencing for clinical management. Cancer 2016;122 : 3838–3847.
  74. Bagante F, Ruzzenente A, Conci S, Rusev BC, Simbolo M, Campagnaro T, et al. Patterns of gene mutations in bile duct cancers: is it time to overcome the anatomical classification? HPB (Oxford) 2019;21 : 1648–1655.
  75. Zhang Y, Ma Z, Li C, Wang C, Jiang W, Chang J, et al. The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers. Nat Commun 2022;13 : 3061.
  76. Huang Y-H, Zhang CZ-Y, Huang Q-S, Yeong J, Wang F, Yang X, et al. Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma. J Hepatol 2021;74 : 838–849.
  77. Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN, Padmanabhan N, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov 2017;7 : 1116–1135.
  78. Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I, Yu W, et al. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat Genet 2012;44 : 690–693.
  79. Chan-On W, Nairismägi M-L, Ong CK, Lim WK, Dima S, Pairojkul C, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet 2013;45 : 1474–1478.
  80. Jusakul A, Kongpetch S, Teh BT. Genetics of Opisthorchis viverrini-related cholangiocarcinoma. Curr Opin Gastroenterol 2015;31 : 258–263.
  81. Farshidfar F, Zheng S, Gingras MC, Newton Y, Shih J, Robertson AG, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles. Cell Rep 2017;18 : 2780–2794.
  82. Simile MM, Bagella P, Vidili G, Spanu A, Manetti R, Seddaiu MA, et al. Targeted therapies in cholangiocarcinoma: Emerging evidence from clinical trials. Medicina (Kaunas) 2019;55 : 42.
  83. Gupta A, Kurzrock R, Adashek JJ. Evolution of the targeted therapy landscape for cholangiocarcinoma: Is cholangiocarcinoma the “NSCLC” of GI oncology? Cancers (Basel) 2023;15. doi:10.3390/cancers15051578
  84. Sia D, Tovar V, Moeini A, Llovet JM. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 2013;32 : 4861–4870.
  85. Xiang X, Liu Z, Zhang C, Li Z, Gao J, Zhang C, et al. IDH mutation subgroup status associates with intratumor heterogeneity and the tumor microenvironment in intrahepatic cholangiocarcinoma. Adv Sci (Weinh) 2021;8: e2101230.
  86. Vogel A, Segatto O, Stenzinger A, Saborowski A. FGFR2 inhibition in cholangiocarcinoma. Annu Rev Med 2023;74 : 293–306.
  87. Angerilli V, Fornaro L, Pepe F, Rossi SM, Perrone G, Malapelle U, et al. FGFR2 testing in cholangiocarcinoma: translating molecular studies into clinical practice. Pathologica 2023;115 : 71–82.
  88. Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol 2019;16 : 105–122.
  89. Neumann O, Burn TC, Allgäuer M, Ball M, Kirchner M, Albrecht T, et al. Genomic architecture of FGFR2 fusions in cholangiocarcinoma and its implication for molecular testing. Br J Cancer 2022;127 : 1540–1549.
  90. Neilson KM, Friesel R. Ligand-independent activation of fibroblast growth factor receptors by point mutations in the extracellular, transmembrane, and kinase domains. J Biol Chem 1996;271 : 25049–25057.
  91. Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N, Nakamura H, et al. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 2014;59 : 1427–1434.
  92. Graham RP, Barr Fritcher EG, Pestova E, Schulz J, Sitailo LA, Vasmatzis G, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol 2014;45 : 1630–1638.
  93. Patel TH, Marcus L, Horiba MN, Donoghue M, Chatterjee S, Mishra-Kalyani PS, et al. FDA approval summary: Pemigatinib for previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion or other rearrangement. Clin Cancer Res 2023;29 : 838–842.
  94. Gandhy SU, Casak SJ, Mushti SL, Cheng J, Subramaniam S, Zhao H, et al. FDA approval summary: Futibatinib for unresectable advanced or metastatic, chemotherapy refractory intrahepatic cholangiocarcinoma with FGFR2 fusions or other rearrangements. Clin Cancer Res 2023;29 : 4027–4031.
  95. Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21 : 796–807.
  96. Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, et al. Final overall survival efficacy results of ivosidenib for patients with advanced cholangiocarcinoma with IDH1 mutation: The phase 3 randomized clinical ClarIDHy trial. JAMA Oncol 2021;7 : 1669 –⁠ 1677.
  97. Xu S, Cao L, Chen R, Ye C, Li Q, Jiang Q, et al. Differential isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 mutation-related landscape in intrahepatic cholangiocarcinoma. Oncologist 2024;29: e1061–e1072.
  98. Boscoe AN, Rolland C, Kelley RK. Frequency and prognostic significance of isocitrate dehydrogenase 1 mutations in cholangiocarcinoma: a systematic literature review. J Gastrointest Oncol 2019;10 : 751–765.
  99. Casak SJ, Pradhan S, Fashoyin-Aje LA, Ren Y, Shen YL, Xu Y, et al. FDA approval summary: Ivosidenib for the treatment of patients with advanced unresectable or metastatic, chemotherapy refractory cholangiocarcinoma with an IDH1 mutation. Clin Cancer Res 2022;28 : 2733–2737.
  100. Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015;348 : 69–74.
  101. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12 : 252–264.
  102. Kim H, Kim H, Kim R, Jo H, Kim HR, Hong J, et al. Tumor mutational burden as a biomarker for advanced biliary tract cancer. Technol Cancer Res Treat 2021;20 : 15330338211062324.
  103. Center for Drug Evaluation, Research. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. In: U.S. Food and Drug Administration (Internet). FDA; 9 Aug 2024 (cited 25 Mar 2025). Available: https://www.fda.gov/drugs/resou- rces-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication
  104. Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 2020;20 : 16.
  105. Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan M, Rodriguez L, Gallagher PS, et al. FDA Approval Summary: Pembrolizumab for the Treatment of Tumor Mutational Burden-High Solid Tumors. Clin Cancer Res 2021;27 : 4685–4689.
  106. Center for Drug Evaluation, Research. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. In: U.S. Food and Drug Administration (Internet). FDA; 9 Aug 2024 (cited 25 Mar 2025). Available: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors
  107. Yang X, Lian B, Zhang N, Long J, Li Y, Xue J, et al. Genomic characterization and immunotherapy for microsatellite instability-high in cholangiocarcinoma. BMC Med 2024;22 : 42.
  108. OncoKBTM MSK’s Precision Oncology Knowledge Base. In: OncoKBTM (Internet). (cited 26 Mar 2025). Available: https://www. oncokb.org/
  109. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11 : 3887–3895.
  110. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 2002;99 : 12293 –⁠ 12297.
  111. Deng M, Li SH, Fu X, Yan XP, Chen J, Qiu YD, et al. Relationship between PD-L1 expression, CD8+ T-cell infiltration and prognosis in intrahepatic cholangiocarcinoma patients. Cancer Cell Int 2021;21 : 371.
  112. Tian L, Ma J, Ma L, Zheng B, Liu L, Song D, et al. PD-1/PD-L1 expression profiles within intrahepatic cholangiocarcinoma predict clinical outcome. World J Surg Oncol 2020;18 : 303.
  113. Walter D, Herrmann E, Schnitzbauer AA, Zeuzem S, Hansmann ML, Peveling-Oberhag J, et al. PD-L1 expression in extrahepatic cholangiocarcinoma. Histopathology 2017;71: 383–392.
  114. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 2012;366 : 707–714.
  115. Li W, Cui Y, Yin F, Peng L, Liu X, Shen Y, et al. BRAF mutation in Chinese biliary tract cancer patients. J Clin Oncol 2020;38: e16678 –⁠ e16678.
  116. Menzies AM, Long GV, Murali R. Dabrafenib and its potential for the treatment of metastatic melanoma. Drug Des Devel Ther 2012;6 : 391–405.
  117. Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 2013;31 : 482–489.
  118. Center for Drug Evaluation, Research. FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. In: U.S. Food and Drug Administration (Internet). FDA; 9 Aug 2024 (cited 27 Mar 2025). Available: https://www.fda.gov/drugs/ resources-information-approved-drugs/  fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid
  119. Zhang H, Berezov A, Wang Q, Zhang G, Drebin J, Murali R, et al. ErbB receptors: from oncogenes to targeted cancer therapies. J Clin Invest 2007;117 : 2051–2058.
  120. Hudis CA. Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 2007;357 : 39–51.
  121. Galdy S, Lamarca A, McNamara MG, Hubner RA, Cella CA, Fazio N, et al. HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target? Cancer Metastasis Rev 2017;36 : 141–157.
  122. Kim H, Kim R, Kim HR, Jo H, Kim H, Ha SY, et al. HER2 aberrations as a novel marker in advanced biliary tract cancer. Front Oncol 2022;12 : 834104.
  123. Javle M, Borad MJ, Azad NS, Kurzrock R, Abou-Alfa GK, George B, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol 2021;22 : 1290–1300.
  124. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018;15 : 731–747.
  125. Demols A, Rocq L, Perez-Casanova L, Charry M, De Nève N, Ramadhan A, et al. A two-step diagnostic approach for NTRK gene fusion detection in biliary tract and pancreatic adenocarcinomas. Oncologist 2023;28: e520–e525.
  126. Scott LJ. Larotrectinib: First global approval. Drugs. 2019;79 : 201–206.
  127. Paratala BS, Chung JH, Williams CB, Yilmazel B, Petrosky W, Williams K, et al. RET rearrangements are actionable alterations in breast cancer. Nat Commun 2018;9 : 4821.
  128. Adashek JJ, Desai AP, Andreev-Drakhlin AY, Roszik J, Cote GJ, Subbiah V. Hallmarks of RET and co-occuring genomic alterations in RET-aberrant cancers. Mol Cancer Ther 2021;20 : 1769–1776.
  129. Augustin J, Gabignon C, Scriva A, Menu L, Calmel C, Scatton O, et al. Testing for ROS1, ALK, MET, and HER2 rearrangements and amplifications in a large series of biliary tract adenocarcinomas. Virchows Arch 2020;477 : 33–45.
  130. Trachu N, Sirachainan E, Larbcharoensub N, Rattanadech W, Detarkom S, Monnamo N, et al. Molecular alterations and clinical prognostic factors for cholangiocarcinoma in Thai population. Onco Targets Ther 2017;10 : 4955–4968.
  131. Valery M, Facchinetti F, Malka D, Ducreux M, Friboulet L, Hollebecque A. Cholangiocarcinoma with STRN-ALK translocation treated with ALK inhibitors. Dig Liver Dis 2021;53 : 1664–1665.
  132. Huang S, Li D, Huang Y, Lu G, Tian Y, Zhong X, et al. An unresectable and metastatic intrahepatic cholangiocarcinoma with EML4-ALK rearrangement achieving partial response after first-line treatment with ensartinib: a case report. Front Oncol 2023;13 : 1191646.
Labels
Anatomical pathology Forensic medical examiner Toxicology
EDITORIAL
INTERVIEW
MONITOR
Cholangiopathies from a Pathologist‘s Perspective: The Role of Liver Biopsy in Routine Diagnostic Practice
The Role of Endoscopy in the Diagnosis of Bile Duct Strictures
Pitfalls of extrahepatic bile duct cytology
Solitary fibrous tumor of the pancreas in a patient with tumor duplicity: a case report
Article was published in

Czecho-Slovak Pathology

Issue 3
2025 Issue 3
Most read in this issue
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#